Transplacental hemophilia A and prophylactic treatment with intravenous immunoglobulin and recombinant factor VIIa in the newborn period

AbstractIt is currently debated whether the mechanism of action of therapeutic doses of recombinant factor VIIa (rFVIIa, Novo-Seven) relies on the tissue factor (TF)-independent activity of the enzyme. The present study was conducted to investigate the in vivo hemostatic effects of rFVIIa and 3 analogs thereof with superior intrinsic activity (FVIIaIIa, K337A-FVIIaIia, and M298Q-FVIIa) in mice with antibody-induced hemophilia A. A highly significant dose response was observed for the bleeding time and blood loss for each of the rFVIIa variants. The bleeding time and blood loss were normalized after administration of 10 mg/kg rFVIIa, 3 mg/kg K337A-FVIIaIia, and 3 mg/kg M298Q-FVIIa, indicating a potency of these FVIIa analogs 3-4 times above that of rFVIIa in FVIII-depleted mice. The different in vivo potencies of the various forms of FVIIa could not be explained by the pharmacokinetics. Histopathological evaluation of kidneys revealed no signs of treatment-related pathological changes even after treatment with the superactive variants. The fact that FVIIa analogs with enhanced intrinsic activity are more efficacious in the murine hemophilia A model strongly suggests that the TF-independent procoagulant activity of FVIIa contributes to its clinical hemostatic effect. (Blood. 2003; 102:3615-3620)

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Inhibition of fibrinolysis by recombinant factor VIIa in plasma from patients with severe hemophilia A

Blood ◽

10.1182/blood.v99.1.175 ◽

2002 ◽

Vol 99 (1) ◽

pp. 175-179 ◽

Cited By ~ 117

Author(s):

Ton Lisman ◽

Laurent O. Mosnier ◽

Thierry Lambert ◽

Evelien P. Mauser-Bunschoten ◽

Joost C. M. Meijers ◽

...

Keyword(s):

Hemophilia A ◽

Recombinant Factor Viia ◽

Factor Viia ◽

In Vitro Study ◽

Clot Lysis ◽

Severe Hemophilia ◽

Large Variability ◽

Lysis Time ◽

Clot Lysis Time

Recombinant factor VIIa (rFVIIa) is a novel prohemostatic drug for patients with hemophilia who have developed inhibitory antibodies. The postulation has been made that hemophilia is not only a disorder of coagulation, but that hyperfibrinolysis due to a defective activation of thrombin activatable fibrinolysis inhibitor (TAFI) might also play a role. In this in vitro study, the potential of rFVIIa to down-regulate fibrinolysis via activation of TAFI was investigated. rFVIIa was able to prolong clot lysis time in plasmas from 17 patients with severe hemophilia A. The prolongation of clot lysis time by rFVIIa was completely abolished by addition of an inhibitor of activated TAFI. The concentration of rFVIIa required for half maximal prolongation of clot lysis time (Clys½-VIIa) varied widely between patients (median, 73.0 U/mL; range, 10.8-250 U/mL). The concentration of rFVIIa required for half maximal reduction of clotting time (Cclot½-VIIa) was approximately 10-fold lower than the Clys½-VIIa value (median, 8.4 U/mL; range, 1.7-22.5 U/mL). Inhibition of TFPI with a polyclonal antibody significantly decreased Clys½-VIIa values (median, 2.6 U/mL; range, 0-86.9 U/mL), whereas Cclot½-VIIa values did not change (median, 7.2 U/mL; range, 2.2-22.5 U/mL). On addition of 100 ng/mL recombinant full-length TFPI, a nonsignificant increase of Clys½-VIIa values was observed (median, 119.2 U/mL; range, 12.3-375.0 U/mL), whereas Cclot½-VIIa values did not change (median, 8.8 U/mL; range, 2.6-34.6 U/mL). In conclusion, this study shows that rFVIIa both accelerates clot formation and inhibits fibrinolysis by activation of TAFI in factor VIII-deficient plasma. However, a large variability in antifibrinolytic potential of rFVIIa exists between patients.

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Postoperative Bleeding in a Sufficiently Substituted Patient with Severe Hemophilia A: Successful Therapy with Administration of Recombinant Factor VIIa

30th Hemophilia Symposium Hamburg 1999 ◽

10.1007/978-3-642-18240-2_49 ◽

2001 ◽

pp. 336-341

Author(s):

H. J. Siemens ◽

S. Brückner ◽

J. Gille ◽

A. Martinez-Schramm ◽

M. Ruslies ◽

...

Keyword(s):

Hemophilia A ◽

Recombinant Factor Viia ◽

Factor Viia ◽

Postoperative Bleeding ◽

Severe Hemophilia ◽

Successful Therapy

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Acquired Hemophilia A: Clinical Features, Surgery and Treatment of 34 Cases, and Experience of Using Recombinant Factor VIIa

Clinical and Applied Thrombosis/Hemostasis ◽

10.1177/1076029608331227 ◽

2009 ◽

Vol 16 (3) ◽

pp. 294-300 ◽

Cited By ~ 27

Author(s):

Manijeh Lak ◽

Ramezan Ali Sharifian ◽

Katayon Karimi ◽

Hassan Mansouritorghabeh

Keyword(s):

Clinical Features ◽

Hemophilia A ◽

Recombinant Factor Viia ◽

Factor Viia ◽

Acquired Hemophilia A ◽

Acquired Hemophilia

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Enhanced in vitro procoagulant and antifibrinolytic potential of superactive variants of recombinant factor VIIa in severe hemophilia A

Journal of Thrombosis and Haemostasis ◽

10.1046/j.1538-7836.2003.00444.x ◽

2003 ◽

Vol 1 (10) ◽

pp. 2175-2178 ◽

Cited By ~ 21

Author(s):

T. Lisman ◽

P. G. De Groot ◽

T. Lambert ◽

R. Rojkjaer ◽

E. Persson

Keyword(s):

Hemophilia A ◽

Recombinant Factor Viia ◽

Factor Viia ◽

Severe Hemophilia

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Recombinant Factor VIIa–Mediated Activation of Prothrombin Complex Concentrates

Clinical and Applied Thrombosis/Hemostasis ◽

10.1177/1076029616663848 ◽

2016 ◽

Vol 23 (3) ◽

pp. 211-220

Author(s):

Nasiredin Sadeghi ◽

Massimo Iacobelli ◽

Behroz Vaziri ◽

Daniel Kahn ◽

Debra Hoppensteadt ◽

...

Keyword(s):

Protein Complex ◽

Hemophilia A ◽

Recombinant Factor Viia ◽

Factor Viia ◽

Final Concentration ◽

Complete Conversion ◽

Prothrombin Complex Concentrates ◽

Total Conversion ◽

Activation Profile

Recombinant factor VIIa (rFVIIa) is used in the management of bleeding in patients with hemophilia. A generic biosimilar version of NovoSeven is also developed (AryoSeven). To compare the activation profile of NovoSeven and AryoSeven, 2 commercially available protein complex concentrates (PCCs) were used. Profilnine activated by RecombiPlasTin 2G resulted in conversions of prothrombin to prethrombin and thrombin at 5 to 30 minutes. However, addition of rFVIIa at final concentration range of 0.25 to 0.5 µg/mL to the same mixture resulted in total conversion of prothrombin to thrombin with a doublet at 36 kDa. Recombinant factor VIIa alone did not generate thrombin in native Beriplex, and the addition of rFVIIa to Beriplex failed to generate thrombin. Beriplex activated by RecombiPlasTin 2G resulted in complete conversion of prothrombin to thrombin. Both NovoSeven and AryoSeven exhibited similar activation profiles. These studies indicate that the activation of PCCs by both rFVIIa preparations results in comparable generation of thrombin.

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An Antibody to Tissue Factor Pathway Inhibitor (PF-06741086) in Combination with Recombinant Factor VIIa Increases Hemostasis in Hemophilia Plasma without Excessive Thrombin Generation

Blood ◽

10.1182/blood.v128.22.2566.2566 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2566-2566 ◽

Cited By ~ 4

Author(s):

Swapnil Rakhe ◽

Sunita Patel Hett ◽

John E. Murphy ◽

Debra D Pittman

Keyword(s):

Inhibitory Activity ◽

Thrombin Generation ◽

Tissue Factor Pathway Inhibitor ◽

Hemophilia A ◽

Recombinant Factor Viia ◽

Factor Viia ◽

Lag Time ◽

Hemophilia B ◽

Extrinsic Pathway ◽

Tissue Factor Pathway

Abstract Hemophilia is a hereditary bleeding disorder caused by intrinsic coagulation pathway deficiencies of Factor VIII (hemophilia A) or Factor IX (hemophilia B). Tissue factor pathway inhibitor (TFPI) is a Kunitz-type serine protease inhibitor that negatively regulates thrombin generation within the extrinsic pathway of coagulation. In hemophilia patients the extrinsic pathway remains intact and thus augmentation of this pathway may circumvent the clotting deficiency in hemophilia. PF-06741086, a monoclonal antibody that binds to and neutralizes the inhibitory activity of TFPI is being developed as a potential treatment for bleeding disorders including hemophilia A and hemophilia B with and without inhibitors. Currently, treatment of inhibitor patients is managed by bypass treatments, such as recombinant Factor VIIa (rFVIIa). The effect of PF-06741086 on thrombin generation in the presence of increasing concentrations of rFVIIa (0.0002 to 20 µg/mL) was studied in severe hemophilia A plasma. A dose-dependent increase in thrombin generation was observed over vehicle control with the addition of rFVIIa to the hemophilia plasma. Addition of a fixed concentration of PF-06741086 (16 µg/mL) in combination with rFVIIa resulted in an increase in thrombin generation including higher peak thrombin and shortening of lag time compared to rFVIIa alone. The TGA profiles with the combination of PF-06741086 and rFVIIa at 0.2, 2, and 20 µg/mL were similar suggesting a saturation of mechanism at these concentrations. The combination of PF-06741086 and rFVIIa restored thrombin generation to normal plasma levels at all rFVIIa concentrations examined. The TFPI inhibitory activity of PF-06741086 on thrombin generation in the presence and absence of rFVIIa was further studied in additional hemophilia A plasmas, including hemophilia A plasmas with inhibitors and hemophilia B plasma. All donors had less than 1% coagulation factor activity. A rFVIIa concentration of 2 µg/mL was selected because it corresponded to plasma levels that could be observed following dosing of FVIIa and because the thrombin generation response in hemophilia plasma was similar with FVIIa added to hemophilia A plasma at 0.2, 2 and 20 µg/mL. The concentration of PF-06741086 was 16 µg/mL in these studies. The effect of PF-06741086 on thrombin generation was also measured in non-hemophilic plasma which would have the full complement of coagulation factors. The addition of PF-06741086 alone or in combination with rFVIIa to hemophilia A and B plasma resulted in an increase in thrombin generation including higher peak thrombin concentration and shortening of lag time compared to addition of rFVIIa alone. In hemophilic plasma samples with inhibitors (3 - 1261 Bethesda Units), PF-06741086 alone also restored thrombin generation. A minimal additive effect in peak thrombin generation was observed with the combination of PF-06741086 (16 µg/mL) and 2 µg/mL rFVIII. The midpoint peak thrombin levels achieved with PF-06741086 alone or in combination with rFVIIa were similar to those observed in non-hemophilic plasma and did not exceed the level observed in non-hemophilic plasma dosed with PF-06741086. To summarize, use of rFVIIa in combination with PF-06741086 results in increased thrombin generation in hemophilia A, hemophilia B and inhibitor plasmas without inducing excessive coagulation. Disclosures Rakhe: Pfizer: Employment. Hett:Pfizer: Employment. Murphy:Pfizer: Employment. Pittman:Pfizer: Employment.

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